Monoclonal antibodies (mAbs), which are now more frequently administered by subcutaneous (SC) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. Preclinical evaluations of mAbs to be administered by SC injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of PK/PD outcomes needed to select clinical doses for first-in-human studies. Despite extensive efforts, no preclinical model has been identified to date that accurately predicts clinical outcomes for these SC injections. We have addressed this deficiency with a novel in vitro instrument, termed Scissor, to model events occurring at the SC injection site and now further validated this approach using a set of eight mAbs for which clinical PK/PD outcomes have been obtained. Diffusion of these mAbs from the Scissor system injection cartridge into a large volume physiological buffer, used to emulate mAb movement from the SC injection site into the systemic circulation, provided distinct profiles when monitored over a 6 h period. Curve-fitting analysis of these profiles using the Hill equation identified parameters that were used, along with physicochemical properties for each mAb, in a partial least squares analysis to define a relationship between molecule and formulation properties with clinical PK outcomes. The results demonstrate that parameters of protein charge at neutral pH and isoelectric point (pI) along with combined formulation properties such as viscosity and mAb concentration can dictate the movement of the mAb from the injection cartridge to infinite sink compartment. Examination of profile characteristics of this movement provided a strong predictive correlation for these eight mAbs. Together, this approach demonstrates the feasibility of this in vitro modelling strategy as a tool to identify drug and formulation properties that can define the performance of SC injected medicines and provide the potential for predicting clinical outcomes that could be useful for formulation selection and a first-in-human clinical dosing strategy.